Renal vasodilators. The role of the 4-substituent in isoquinolin-3-ol cardiovascular agents: 4-ureido derivatives of isoquinolin-3-ol with selective renal vasodilator properties.

The synthesis and cardiovascular evaluation of a series of isoquinolin-3-ol derivatives bearing a variety of nitrogen substituents (amino, acylamino, carbamate, and ureido) at C-4 are described. Certain of these compounds have a selective renal vasodilating profile and have minimal effects on arterial blood pressure or heart rate when administered intravenously in the instrumented anesthetized dog. The most potent renal vasodilator in the series is 4-(allylureido)-6,7-dimethoxyisoquinolin-3-ol (38), which at a dose of 1.2 mg/kg iv produces a 97% maximal increase in renal blood flow without significant hypotensive or chronotropic effects. Structure-activity observations on the nature of the 4-substituent and the alkoxy substitution pattern in the aromatic ring of the isoquinolinol nucleus are discussed.

Cardiotonic agents. Synthesis and inotropic activity of a series of isoquinolin-3-ol derivatives.

A series of isoquinolin-3-ol derivatives (II) was prepared as analogues of the clinical cardiotonic agent bemarinone (ORF 16600, I). Although in many respects the structural requirements for the cardiotonic activity of II are similar to those of bemarinone, certain differences between the series were noted. Our structure-activity studies show that II is less sensitive to alkoxy-substitution effects than is I, and more significantly, 4-substitution of II by alkyl groups, halogen, or alkanecarboxylic acid derivatives enhances cardiotonic activity in II in contrast to I, wherein analogous substitution eliminated activity. A linear correlation between contractile force (CF) increase and cyclic nucleotide phosphodiesterase fraction III (PDE-III) inhibition by the title compounds was determined. The isoquinoline derivatives were characteristically short-acting cardiotonic agents with good potency and selectivity.

Inhibitors of dihydropteroate synthase: substituent effects in the side-chain aromatic ring of 6-[[3-(aryloxy)propyl]amino]-5-nitrosoisocytosines and synthesis and inhibitory potency of bridged 5-nitrosoisocytosine-p-aminobenzoic acid analogues.

We previously reported that 6-(methylamino)-5-nitrosoisocytosine (5) is a potent inhibitor (I50 = 1.6 microM) of Escherichia coli dihydropteroate synthase. It was noted that 6-amino substituents larger than methyl were detrimental to binding, although the adverse steric effect could be overcome by a positive ancillary binding contribution of a phenyl ring attached at the terminus of certain 6-alkylamino substituents. We selected the 6-[[3-(aryloxy)propyl]amino]-5-nitrosoisocytosine structure as a parent system and explored the effects of aromatic substituents on synthase inhibition. The nature of the aryl substitution influences binding, as shown by a 30-fold range of inhibitory potencies observed for the 15 aryl analogues (I50 values = 0.6-18 microM), although there is no apparent correlation between synthase inhibition and the electronic or hydrophobic characteristics of the aryl substituents. To explore the possibility that the aryl ring of these inhibitors might interact with the synthase binding site for the substrate p-aminobenzoic acid (PABA), three compounds were synthesized in which a PABA analogue is bridged to the nitrosoisocytosine moiety by linkage to an amino group at C-6 of the isocytosine. The bridged analogues significantly inhibited the synthase (I50 values = 2.5-8.9 microM) but were of unexceptional potency compared with other members of the (aryloxy)propyl series. Structure-activity considerations and inhibition kinetics did not support the PABA binding site as the synthase region that interacts with the aryl ring of these inhibitors. Despite the potent synthase inhibition exhibited by many of the nitrosoisocytosines studied, none of the 18 new analogues showed significant antibacterial activity.

Monocyclic pteridine analogues. Inhibition of Escherichia coli dihydropteroate synthase by 6-amino-5-nitrosoisocytosines.

A variety of 5,6-disubstituted isocytosine derivatives were evaluated in vitro as inhibitors of dihydropteroate synthase from Escherichia coli. A number of 6-(alkylamino)-5-nitrosoisocytosines have in vitro potency equivalent with or superior to that of therapeutically effective sulfonamide inhibitors of the synthase. The sulfonamide drugs are known to compete for the p-aminobenzoic acid binding site of the synthase, and kinetic analysis of inhibition of the synthase by 6-(methylamino)-5-nitrosoisocytosine (16; I50 = 1.6 microM) and by the 6-(3-phenoxypropyl) amino analogue (33; I50 = 3.7 microM) indicated that the nitrosoisocytosine inhibitors compete with the pteridine substrate for the enzyme. Structure-activity studies demonstrated that the enzyme surface has a low tolerance for steric bulk in the region surrounding the isocytosine 6-amino function. However, this steric intolerance may be counterbalanced to a significant degree by positive allosteric interactions achieved by certain analogues that have a 6-(omega-phenylalkyl)amino substituent. For example, 6-[(7-phenylheptyl)amino]-5-nitrosoisocytosine (28) is as effective an inhibitor (I50 = 1.4 microM) as the 6-methylamino compound 16. Although several members of the 5-nitroso series were potent synthase inhibitors, none of the nitrosoisocytosines exhibited significant antibacterial activity. This observation may reflect poor transport of these compounds through the bacterial cell wall or, alternatively, may result from a rapid metabolic inactivation process.

Opioid receptor interactions and conformations of the 6 alpha and 6 beta epimers of oxymorphamine. Solid-state conformation of 6 alpha-oxymorphamine.

The affinities of the oxymorphamine epimers for mu and delta opioid receptors were determined in vitro. The 6 alpha and 6 beta epimers are potent mu-selective ligands with similar receptor-binding profiles. The relatively undramatic effect of C-6 chirality on receptor interactions is intriguing in view of the recently demonstrated profound influence of C-6 chirality on ring-C solution conformations (ring C is a chair conformer in the beta epimer but adopts a twist-boat conformation in the alpha epimer) and prompted the determination of the crystal structure of alpha-oxymorphamine. The crystal structure showed that ring C in this epimer also adopts a twist-boat conformation in the solid state. Molecular modeling of the oxymorphamines in the preferred ring-C conformations (alpha = boat, beta = chair) demonstrated that the 6-amino groups project to spatial loci significantly more proximal (0.35 A) than would be the case (2.2 A) if both epimers adopted chair conformations for ring C. Consequently, although the epimeric oxymorphamines differ in ring-C conformation, the principle potential heteroatomic binding sites in each epimer are oriented similarly, which may be partly responsible for the lack of dramatic differences in receptor binding profiles.

Synthesis of bridged catechol-homocysteine derivatives as potential inhibitors of catechol O-methyltransferase.

Catechol derivatives, covalently joined to homocysteine by sulfide or sulfonium linkages, were synthesized as potential catechol O-methyltransferase multisubstrate inhibitors which might bridge the enzymatic binding sites for the catechol substrate and the amino acid portion of the methyl donor S-adenosylmethionine. These compounds were found to be less effective inhibitors than the product inhibitor S-adenosylhomocysteine.